Medical Targets and The Therapeutic Development in Parkinson’s Disease (CHAPTER 2)

Literature Review

Introduction

Parkinson’s disease was first recognized in 1817 as a neurodegenerative disorder which is characterized by the chronic loss of motor function. This mental disorder usually starts appearing between the ages of 50-80 years of age with a male to female preponderance. The disorder is significantly associated with depletion of dopaminergic cells in the substantia nigra. Dopamine has an important role in the movement and deficiency in production of movement may cause disinhibition of motor movements like motor speech movements (Bhatnagar, 2008). In previous studies, the most attention has been given to degeneration of dopamine-producing cells in a particular portion of the midbrain called the substantia nigra and they no longer generate dop­amine. Thus the clinical symptoms start appearing. Early diagnosis process of Parkinson’s disease involves nerves in the auto­nomic nervous system in the gastrointestinal tract and heart, even before cells in the brain are impacted (Orimo et al, 2007). In classis, Parkinson’s disease is found to be a systematic condition affecting neurons constituent cellular inclusion is alpha-synuclein (AS) that is insoluble (Shults, 2006). The most common clinical features related with PD are Bradykinesia (slowness of movement), Tremor, and rigidity (resistance) and Postural deformities, postural instability and Freezing (Jankovic, 2008). Buy writing paperfrom experts.

Treatment Approaches for Parkinson’s disease

Different studies have suggested that treatment approach for PD must be made on the base of individual and not same treatment should apply for everyone. Studies have also suggested effective treatments for the symptoms of PD which has recently significantly expanded. The advances made in treatment of PD are observed both in pharmacotherapy and neurosurgical approaches. As a result of these advanced treatment of PD symptoms patient with PD now enhance the quality of life and even extend the survival. From the end of last decade, a number of new medications for the treatment are now available and providing expanded previously limited medications for PD (Rezak, 2007).

Since this paper mainly aims to review the treatments of PD, next section of the paper presents medical treatment options for the Parkinson’s patients and also discusses data from clinical studies. These medical options mainly discuss pharmacological treatment available for PD patients. Other treatment approaches will be discussed in latter section of the paper.

The pharmacological treatment of PD is broadly divided into three different major groups such as

Protective, to interfere with the pathologic mechanisms of the disease;

Protective Treatment for PD

Recent studies suggest that PD can be identified even though it is not fully developed with its symptoms. For this, they have suggested that it can be done when the cardinal manifestations are least or even absent. They have further pointed out that an olfactory impairment, constipation, a rapid eye movement behavior disorder, abnormalities in cardiac dopamine neuroimaging, and other genetic factors can be initial possible characteristics of PD that precede the early stages of the classic motor features of the disease. The identification of PD before the early stage of a motor dysfunction may possibly allows putative disease-modifying therapy. A disease- modifying drug is assumed to be active in reducing the progression of symptoms (Kincses& Vecsei, 2010).

The National Institutes of Health has been working to identify Neuroprotective Agents for Parkinson’s (CINAPS) with a view to the organized collection and evaluation of information about candidate interventions. In this regard, NINDS-sponsored trials have tested four compounds: creatine, minocycline, coenzyme Q10 and neuroimmunophilin ligand (Klivényi& Vécsei, 2009).

Creatine, a nutritional supplement uses neuroprotective is affective in vivo against number of neurotoxins. Creatine is transformed into phosphocreatine and is able to transfer a phosphoryl group to adenosine diphosphate. In phase 3, a long-term study for multicenter, double-blind, placebo-controlled study on PD is still continuing (Klivenyi& Vecsei, 2010). Minocycline is a tetracycline antibiotic and has good brain dissemination. Minocycline has also been shown to slow down microglial related inflammatory, and the apoptotic cascade (Gárdián& Vécsei, 2010).

Coenzyme Q10 is also a nutritional supplement, and an electron acceptor linking mitochondrial complexes I and II/III and a powerful antioxidant that moderately reinstates the role of neurons (BealMF, 2009). GPI-1485 is the neuroimmunophilin ligands, which is helpful to repair and redevelop damaged nerves with no effects on normal nerves (The NINDS NET-PD Investigators, 2007).

The Kynurenine System

Tryptophan which is one of the standard amino acids is metabolized using number of pathways. The serotonergic pathway is the most widely known pathway for the metabolism process. It is the precursor of a pineal hormone, melatonin. L-Kynurenine (KYN) pathway is less known but the main alternative pathway for the tryptophan metabolism. The metabolic cascade has been originally a source of end products, nicotinic acid, nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate (Gárdián& Vécsei, 2010). The significance of KYN family in neurobiology rose with the emergence of quinolinic acid (QUIN) and kynurenic acid (KYNA). L-KYN is an important compound in the pathways because it can be metabolized to other components. By shifting the KYN metabolism toward KYNA formation, it can reduce receptor activation and excitotoxic neuronal damage.

Symptomatic Treatment

Symptomatic treatment provides control over motor and non-motor symptoms with the neuroprotective and minimum side effects. There are number of compounds used for the symptomatic benefits (Horstink et al, 2006). These compounds work differently such as MAO-B inhibitors, Amantadine, Anti-cholinergic Drugs, and Dopamine Agonists, and Levodopa affect Dopaminergic.

The next section discusses the compound mainly affect the Dopamine and also called Dopaminergic Treatment.

Dopaminergic Treatment

MAO-B inhibitors

MAO-B inhibitors have ability to increase dopamine levels in the synapse as they obstruct the MAO-B oxidation of dopamine. MAO-B inhibitors, such as deprenyl and selegiline, are used as antidepressants. Selegiline is used as a putative neuroprotective compound. In the early stage of disease, selegiline monotherapy provides little symptomatic benefit and delays the use of levodopa. The use of selegiline also delays the motor dysfunction and disability.

Amantadine

Amantadine is used as an anti parkinsonian. It helps to releases dopamine from central neurons, and delays the absorption of dopamine by neural cells, obstructs NMDA receptors and makes an anti cholinergic effect. Its effects on tremor are minimal and cautious use is required because it may cause hallucinations and confusion. It has some other side effects such as urinary hesitancy, leg edema and reticular livedo but it can be used at every stage of PD (Kincses& Vecsei, 2010).

Anti-Cholinergic Drugs

Anti-cholinergic has effects in reducing tremor but has little effect on Bradykinesia, rigidity. It is administered to younger patients with PD where the cognitive function is preserved. Since there are some side effects such as confusion, hallucinations, tachycardia, dry mouth and eyes, urinary retention, sweating and. However, it is proved to be effective in reducing symptoms but its use is frequently decreased due to its side effects. Anti-Cholinergic Drugs available today are trihexyphenidyl, benztropine and procyclidine, orphenadrine and biperiden (Diaz& Waters, 2009).

Dopamine Agonists

Dopamine agonists are used as first treatment to overcome early symptoms of PD and used aside with levodopa for patients with advanced disease. They are less effective than levodopa. Today, there is non-ergot-derived drug available which is not commonly used because there are more severe side effects of them.

Levodopa

Levodopa is the precursor of dopamine and rapidly releases carboxyl in the periphery. It is therefore controlled in blend with a peripheral inhibitor of dopa decarboxylase (DDCI), carbidopa/benserazide. Levodopa has long been using for improving the motor features of PD. It is effective to improve Bradykinesia and rigidity, but is not effective for tremor on all patients. Levodopa is metabolized peripherally by COMT that produces 3-O-methyldopa. Peripheral DDC and COMT inhibitors function to prolong the half-life of levodopa, and improve the delivery of levodopa to the brain, where it is transformed to dopamine. Entacapone is an elective, reversible, peripherally acting COMT inhibitor. To lcapone is a selective, centrally and peripherally acting, reversible COMT inhibitor. To lcapone improves the half-life of levodopa more than entacapone does. Its main side effect is that it fails hepatic (Olanow et al, 2009).

b. Non-Dopaminergic Treatment

Since the roles of neurotransmitters and neuromodulators are identified in the motor and non-motor symptoms. Non-dopamine treatment focuses on multiple non-dopaminergic pathways and the receptors in the striatal output. Since more than 90% of the neurons in the striatum are GABAergic medium-sized spiny neurons. Striatopallidal neurons have dopamine D2 receptors, while striatonigral neurons have dopamine D1 receptors (Kincses& Vecsei, 2010). Adenosine A2A receptors are selectively located on striatopallidal neurons ((Kincses& Vecsei, 2010). The co-localization of adenosine A2A and dopamine D2 receptors in the striatopallidal neurons gives the anatomical basis for over-activation of the indirect pathway in PD by the activation of adenosine A2A receptors (Kincses& Vecsei, 2010). This functional interaction has suggested new therapeutic approaches for PD, based on the use of selective A2A receptor antagonists (Jenner et al, 2009). In addition, NMDA antagonists are also considered as treatment option for non-dopaminergic treatment which induces a state called dissociative anesthesia.

c. Non-motor Problems

Non-motor problems occur with patients of PD include sleep, and autonomic and sensory domains disability these symptoms occurs due to neuropsychiatric effects. Non-motor symptoms of PD are very important because they determine the patients’ quality of life. These symptoms of non-motor are caused by non-dopaminergic europathological changes and treatment with dopaminergic agents or drugs. Therefore it is essential to identify these phenomena, as some non-motor symptoms can precede motor mutilation. The treatment of these non-motor symptoms includes dopaminergic treatment that works to increase or reduce the dopamine responsiveness of the symptom. Patients with urologic problems are prescribed for urologic evaluation. Urinary tract infections are instantly treated.

If first step of the study is analyzed, it shows that levodopa, entacapone and carbidopa are valuable pharmacological treatment options for early PD (Hauser et al, 2009). However, the study about delay in the initial motor complications showed that the time to dyskinesia was remarkably shorter in levodopa, carbidopa and entacapone.

Non-Pharmacology Treatment

As a result of limitation of pharmacological treatment for most neurodegenerative diseases, currently new trends are being made towards developing and new surgical treatment that could be more effective on symptoms and give relief from them (Torresa et al, 2010). There are many studies that stress on the need of parenteral dopaminergic therapy or surgery for patient with complex disease (Schapira, 2007). As far as surgical treatment is concerned it involves implantation of electrodes into the brain to directly use high-frequency electrical stimulation until the occurrence of the symptom of disease is reduced. A distinct and persistent surgery treatment for PD is called Deep Brain Stimulation (DBS). But this option is considered as necessary when pharmacological treatment is no more effective for PD (Torresa et al, 2010). Since DBS is new surgical treatment for PD that deals with the intractable motor symptoms, there is need to discuss how it works and what its effects are.

Deep Brain Stimulation

Deep Brain Stimulation (DBS) usually leads to remarkable improvements in Bradykinesia as well as dyskinesias which are induced by a long use of levodopa (Torresa et al, 2010). DBS can also be considered as an effective alternative option to dopamine therapies and their remarkable complications in advanced PD. Other studies have revealed that DBS is safe and adjustable and DBS is now rationally justified as experiments with animal models of PD in which separate lesions to basal ganglia circuits, and the thalamus (thalamotomy) and globus pallidus have showed improved Parkinson’s disease symptoms. The observations and experiments made guided towards the pulsing electrical currents to extremely specific brain parts such as the sub-thalamic nucleus (STN), so imitating the functional effects of pinpoint removal. Through DBS STN in particular is targeted as high-frequency electrical stimulation to this nucleus successfully restores thalamocortical activity feedback loops. But observational effectiveness of the mechanisms is not known by which electrical stimulation to the thalamus stop abnormal rhythmic oscillations that generate dyskinesias. Studies have suggested the possible effects of DBS on potentials of neuronal membrane and voltage-dependent Ca2+ channels. This enables the DBS to changing the firing pattern, rather than the firing rate, of STN neurons to instantly develop an effect near the electrode’s tip (Chan et al., 2007). Another study suggested that DBS has high-frequency electrical stimulation effects on the axons that carry signals into the STN from other areas, like the primary motor cortex. In order to support this assumption on the base of animal models of PD in which visually stimulated cortical neurons, whose axons reach down the STN, also decreases Parkinson’s disease symptoms as efficiently as conventional DBS did (Histed et al., 2009).

Conclusion of Literature Review

However, there is no absolute treatment of PD but studies indicate that both intervention approaches: pharmacology and surgical treatments are effective to reduce the symptoms. The selection of treatment remarkably depends on the severity and progression rate of disease (Factor& Weiner, 2008). Drugs are effective in initial stage to overcome the symptoms and as PD progresses additional drug provision is necessary made to control the symptoms (Schapira, 2007). The option for surgical treatment like DBS is considered as necessary when disease is complex and drugs are no more effective (Schapira, 2007).